Putting together the cohort of 5,000 will probably take a few years, (assuming it does secure funding); then probably at least another 2 years before the results of any research on the cohort is available. That will hopefully reveal cohorts and give clues at to molecular pathways.

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It would be nice to do some joiny-uppy stuff and have any patients entering clinical trials (such as the Rituximab trial) also get included in this database.

It would be nice to do some joiny-uppy stuff and have any patients entering clinical trials (such as the Rituximab trial) also get included in this database.

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I agree. And like the phrase 'joiny-uppy' too Am wondering if there has been anything with which we might compare. Some other disease that was looked at in this way, in the recent past on such a large scale? What say you Simon my man?

As I examined the history of antecedent epidemics, an interesting thing stood out.
Aside from the doctor or doctors who identified their own outbreak, the incident is never followed up.
Even if others use the name, researchers want to study "In their own backyard"

The name, the entity, the outbreak, and all the evidence gets lost as it shifts from one to the next.
Over and over. It's like throwing all the game pieces off the board, starting back at square one.

Oblivious to what they threw away, when they "moved on".

Some of what they threw away was worth knowing, but since they didn't know how much they had lost,
they called it "progress" anyway.

It would be nice to do some joiny-uppy stuff and have any patients entering clinical trials (such as the Rituximab trial) also get included in this database.

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It's an important point about how information gleaned from clinical trials integrate into big research cohorts like this. I don't know how practical it is to combine them directly: over on the Rituximab thread, Jonathan Edwards commented on the possibility of combining the proposed UCL study with the Norwegian one and said that while it makes good theoretical sense, the more complicated any study becomes, the harder it is to get high quality data. He said in practice it works better to do such things separately.

However, if the UCL study finishes before the cohort recruitment is complete, maybe there is a chance to enroll then UCL patients into the cohort. Could be worth suggesting to UCL, once the study is settled?

Alternatively, the 5k cohort study could be used to explore and build on any UCL findings. Let's say they discover that certain patients respond well to rituximab, and others don't, and they have identified the key factor, eg NK cytotoxicity levels. They could then test for that in the Cohort, to see what proportion of patients generally are likely to respond well to ritux.

I agree. And like the phrase 'joiny-uppy' too Am wondering if there has been anything with which we might compare. Some other disease that was looked at in this way, in the recent past on such a large scale? What say you Simon my man?

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Er, good question. Though in his talk, Stephen Holgate, emphasised how now was the time to study ME/CFS because of the emergence of new techniques, so I don't know if such an in-depth study has been done before, since this is the cutting edge. Maybe that's part of the appeal. Will try to find out if the approach has been used before.

It's an important point about how information gleaned from clinical trials integrate into big research cohorts like this. I don't know how practical it is to combine them directly: over on the Rituximab thread, Jonathan Edwards commented on the possibility of combining the proposed UCL study with the Norwegian one and said that while it makes good theoretical sense, the more complicated any study becomes, the harder it is to get high quality data. He said in practice it works better to do such things separately.

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I agree that trying to add on to a pre-existing trial would have the downside of complicating matters but enrolling patients in what are essentially two separate studies (the trial and this cohort) wouldn't add complexity to either, just more scope for additional analysis. I think it would make sense to include the trial participants in the cohort before they get treated, as a further opportunity to distinguish responders from non-responders, and to have them in a study where they'll be getting longitudinal follow-up (I think) at no extra cost to the Rituximab trial.

I agree that trying to add on to a pre-existing trial would have the downside of complicating matters but enrolling patients in what are essentially two separate studies (the trial and this cohort) wouldn't add complexity to either, just more scope for additional analysis. I think it would make sense to include the trial participants in the cohort before they get treated, as a further opportunity to distinguish responders from non-responders, and to have them in a study where they'll be getting longitudinal follow-up (I think) at no extra cost to the Rituximab trial.

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It's hard to know how feasible this is, not least because right now, neither study is funded (or even applied for in the case or Rtx) so we don't yet know the mechanics. My guess is that, because the 5k cohort is so big, it's tapping into clinics in a big way - which presumably means the BACME clinic network. If so, they will be gathering data from their own regular patients, probably new patients so the time spent on diagnosis etc is time already budgeted for. That means they wouldn't automaticlly welcome having to add a separate group to their study, esp if it meant taking clinician time away from regular clinic work.

Thinking aloud here, one possibility is, if UCL contacts whoever plans the cohort (it's not Stephen Holgate's study AFAIK), they could arrange to recruit for that study via clinics particpating in the cohort (they have to find the patients somewhere, and there are BACME clinics in London). That would minimise any duplication of effort in having patients in both studies. There may be many practical reasons why this wouldn't work, but might be worth discussing the possibility with JE on the Rituximab thread.

I agree that it would be good if the same patients figured in both studies. And potentially, if a mechanism to cooperate easily can be found, it could apply to other UK studies too, eg Julia Newton's work - which is what you were originally suggesting, I think. So that would be another reason to explore this now.

Thank you for this. It is Important to inform people of what really happened. I just finished reading "Osler's Web" for the second time and I'm very interested to hear more a out it.
I feel though that this is important enough to have its own separate thread.

I believe that by the conclusion of the CFI:Lipkin study there will be a significantly new set of players in the field of diagnostic criteria due to the strong advancement in technology and testing medium (serum, urine, saliva, tissue and spinal fluid). Diagnostic testing has ran out of room by trying to find everything in serum for sure. There is probably room in urine and saliva, but spinal fluid and tissue samples will have to be a part of a definitive analysis at some point. Unless some new types of analysis are developed which is very possible. Ultrasound, forms of MRI's and very small tissue samples of tissue and spinal fluid.

Thanks Simon - great article - 15 sounds about right !
Not read all posts but here in Australia lots are now being re- diagnosed with LYME, POTS/OI and EDS -
Ehlers-Danlos Syndrome so these are likely among the 15 along with other CTDs it seems

And I should add that as EDS makes y ou more prone to other illnesses it may be likely that some have EDS AND Lyme disease - the overlap in symptoms will make it hard to differentiate but may explain why some seem to respond well to Lyme treatment while others do not - they may have underlying POTs or EDS so the symptoms never disappear even if the Lyme is treated

Am wondering if there has been anything with which we might compare. Some other disease that was looked at in this way, in the recent past on such a large scale? What say you Simon my man?

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I asked Stephen Holgate who replied:

Cancer is leading the way here. Other complex diseases are following especially Rheumatoid Arthritis, Inflammatory Bowel Disease, Psoriasis, Type 2 Diabetes, Multiple Sclerosis and Alzheimer's Dementia. All very exciting!

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So it is being done, though I'm afraid I don't have any more specifics from the Professor. However, a recent Nature paper on Cancer gives an idea of the approach:

Like the proposed ME/CFS study, it was on a huge scale - looking at 7,000 indiviudal cancer genomes for 30 different types of cancers (ie looking at the specific mutations in each of 7,000 individual's cancer). From this they identified 21 common 'mutational signatures' - a common pattern of DNA mutations eg there is one mutational signature caused by damage from UV radiation. Which is pretty cool.

But it wasn't a case of one mutational signature being linked to one type of cancer. Each person's cancer carried at least two different mutational signatures (and not every individual with the same type of cancer would have exactly the same mutations).

What they found was that some mutational signatures cropped up in many different types of cancer. For instance, one mutational signature common in breast cancer was also found in 16 of the 30 types of cancer studied. Wheras some of the mutational signatures were only ever found in one type of cancer.

So they started off with 30 different types of cancer. But when they looked at the molecular level - specifically at the types of DNA mutations underlying the cancers, they found a very different pattern, with some DNA mutational signatures cropping up in lots of different cancers.

The scientists think that by better understanding the precise mutations involved they will learn a lot about the causal mechanisms of cancer.

This cancer study used some pretty-intensive mathematical computational approaches, which is just the sort of approach that Stephen Holgate has advocated to make sense of a lot of data from 5,000 ME/CFS patients.

Look like ME/CFS is moving to the forefront of science - which is probably where it needs to be if such a complex illness is ever going to be cracked.

Plenty of time to get used to any findings
Putting together the cohort of 5,000 will probably take a few years, (assuming it does secure funding); then probably at least another 2 years before the results of any research on the cohort is available. That will hopefully reveal clusters and give clues at to molecular pathways.

Then at least another few years to nail down the first pathways (assuming they exist). And at least 5 years to find a drug and get it to market. So well over a decade in total, and that's just to tackle some of the disease clusters. We won't be waking up any day soon to discover that we all have one of several new, previously undisovered diseases within ME/CFS - or are orphaned in an undiagnosed mishmash of leftovers.

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Hopefully not only drug treatments will be considered. I would expect that some of the clusters would be amenable to other treatments which do not have such long lead times as drugs, and better safety profiles. Also, some existing drugs with known safety profiles may be useful ('repurposing'), which again can be brought into use relatively quickly.

Hopefully not only drug treatments will be considered. I would expect that some of the clusters would be amenable to other treatments which do not have such long lead times as drugs, and better safety profiles. Also, some existing drugs with known safety profiles may be useful ('repurposing'), which again can be brought into use relatively quickly.

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Yes, drug repurposing could be a shortcut eg rituxmab, if there are any suitable available. What other treatents did you have in mind?

Yes, drug repurposing could be a shortcut eg rituxmab, if there are any suitable available. What other treatents did you have in mind?

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I was thinking of things that some of us already find helpful such as dietary changes and supplements. It's a difficult process working out which foods and supplements help which people, and we may never quite find the optimal mix. Subgrouping patients might help us to do this, so that the interventions are more effective, and maybe even bring about remission or that four-letter c-word...(says to self - go on - say it - OK - cure!)